How can we develop medications that can improve the lives of persons with ASD?

When I am giving talks to families about the research Autism Speaks funds, I am sometimes asked why we are funding a particular study when that study appears to have very little to do with the majority of people who actually are living and struggling with autism. This especially comes up when I am talking about studies involving animal models, brain tissue, and rare genetic conditions. Parents often express their frustration that scientists have not yet developed medications that can improve the quality of life for people with autism, medications that can help a child or adult with autism spectrum disorders (ASD) communicate better or be more comfortable around other people. I realize then that the connection between many of the studies we fund and our goal of developing medications that can help people with autism may not be clear. In this article, I hope to illustrate how many of the individual studies that we fund – which in isolation may not seem relevant – are part of a discovery and development process ultimately aimed at providing medications that can improve the life of individuals with ASD.

I will begin with some background on the process of moving from basic laboratory studies to delivery of a useful medication to the community, a process often referred to as “translational research.” The process of drug discovery begins with identification of a “drug target.” A drug target is a component of a biochemical pathway, sometimes referred to as a “signaling” or “metabolic” pathway. How do we figure out what signaling or metabolic pathways are affected in ASD? One way is to closely examine the actual brain cells of persons with autism, which is only possible with post-mortem brain tissue donated by families (view a recently funded study using post-mortem brain tissue).

Another way is to use animal models (see a perspective on mouse models from Craig Powell) to study the effects of a genetic mutation that is known to result in ASD or ASD symptoms. It has also been useful to start by studying conditions such as Rett syndrome and Fragile X syndrome because the genetics of these conditions are well understood. In addition, we know that these conditions are often associated with autism (e.g., about 30 percent of individuals with Fragile X also have autism). Animal models of these syndromes are becoming well developed, allowing scientists to study how the genetic mutation influences the biochemistry and brain functioning (view a recently funded study of synaptic alterations in the amygdala). These types of studies pointed scientists to specific signaling pathways; for example, a pathway involving two neurotransmitters: GABA and glutamate. These chemicals are crucial for neurons (brain cells) to establish a communication network through the formation of synapses (connections between neurons). Specifically, the genetic mutation alters the amount of these chemicals released in the brain (i.e., too much glutamate), resulting in over-excitation of the neural circuits. This disrupts learning.

Interestingly, at the same time these discoveries were being made, other scientists discovered that many of the genetic mutations that result in autism also disrupt the functioning of the synapse (view a recently funded study of synapse function). The strategy here is to look for common signaling pathways that are disrupted by different risk genes. These pathways offer the best hope for developing a medication that can be helpful not just with one genetic subtype of ASD, but more generally for many individuals who have ASD (even those where an environmental trigger might have been involved).

The process of drug target identification

Once a disrupted pathway or pathways contributing to a condition is discovered, scientists can start testing (“validating”) whether certain medications can restore the functioning of that pathway and improve behavioral functioning in animal models and humans. Another strategy for testing different medications is to examine the effects of the medication on cells (neurons) derived from freshly isolated post-mortem brain tissue that was donated by individuals with autism through Autism Speaks’ Autism Tissue Program.

Currently, several medications that are designed to improve behavioral functioning in autism are being tested in persons with associated genetic disorders such as Rett syndrome, Tuberous Sclerosis, and Fragile X syndrome (view two recently funded human clinical trials of medications for Rett syndrome and Tuberous Sclerosis ). If these medications are found to improve behavioral functioning in individuals with these conditions, plans to study some of these medications with people with ASD will follow. The hope is that because these conditions share some biological and behavioral similarities, these same medications will be more widely effective. At the same time, drawing from what we have learned about the role of glutamate from studies of Fragile X syndrome, Autism Speaks is currently funding a “phase one” or “proof of concept” clinical trial of memantine, a medication that reduces the availability of glutamate, for persons with ASD. As we understand more about the underlying biology of ASD using the strategies described above, there will be more promising leads for new medications that can improve the lives of persons with ASD.

The process from target identification to FDA approval of a new medication is arduous. Animal and human studies are needed to examine safety, side effects, optimal dosing, and other factors (these are referred to as Phase I, II, and III clinical trials). This “drug development pipeline” involves the collaboration among agencies such as the NIH and Autism Speaks that provide research funding; academic scientists who often conduct the high risk research that leads to target identification and validation; pharmaceutical companies who, once a target is validated, have the capability and resources of conducting the larger Phase II and III trials; and the FDA who is responsible for approving the medication for wide usage. This collaboration is essential for drug discovery and development.

Translational research moves findings from the lab to the families. It is one of many diverse areas of research emphasis at Autism Speaks. This type of research provides hope for the future. But, at the same time, we are funding studies that have more immediate impact on people lives. These include studies of novel behavioral and other types of interventions that can be quickly implemented by parents, therapists, and teachers, as well as many others (see examples of recently funded studies on Pivotal Response Training and Cognitive Enhancement Therapy that can have immediate impact. This balance between short- and long-term research is a key part of Autism Speaks’ overall funding strategy.

After 7 1/2 years of dealing with diapers and pull-ups our daughter is fully potty trained. 24 days ago we took both our children who have a diagnosis of ASD PDD NOS, to Ecuador to the American Stem Cell and Anti Aging Center for Stem Cell treatment. The changes, especially with our daughter are dramatic! She is a happy little girl, looking right in our eyes and smiling all the time. She used to tantrum, a lot, and was generally uninterested in interacting at all. Instead of researching towards a drug treatment, which I had tried, why is this not available here and why doesn’t everyone know about it! I am furious as a parent that I happened upon this treatment, and even more furious that there are a couple facilities in the US that offer the treatment ranging from 100,000 to 200,000 US. We paid 20,000 per child. This was their own dormant stem cells, no risks!! How can something like the H1N1 vaccine be rushed through and something like this take another 6-8 years for a billing code. Very sad statement about our government and world in general. This isn’t too good to be true, it is real, our kids are real, and thank God we took a leap of faith and a bank loan and tried it, or I would have been changing pull ups for a long time to come instead of smiling at my daughter and helping our kids on their road to recovery! Wesley Chapel, FL

Why would you be devastated by research? What are you afraid of? This is a huge step forward of the mission of Autism Speaks. The goal is to find the answers, and genetic research holds those answers. Once we have the genetic “causes” we can target approaches & treatments to help and maybe even prevent autism. Why use the word “devastated” ??

Erik

February 7, 2011 at 6:05 pm

just stumbled upon this discussion…but we shouldn’t be looking for “genetic causes”. Our human DNA has remained virtually unchanged in 10,000 years…why is it all of a sudden we are seeing a meteoric rise in autism, heart disease, cancer, etc.? The genetic theory of disease flies in the face of the entire theory of evolution. It can only be explained by environmental “causes”. I am not insensitive to families with autistic children, we have a very dear friend with an autistic child and we see the devastation it brings, and I certainly applaud Autism Speaks for bringing the discussion to the forefront, but we need to understand that we can only get the right answers if we ask the right questions. For the past 100 years we’ve been asking “what illness do I have and how do I treat it?” instead of “why am I sick and how do I get healthy?”

I applaud Autism Speaks to keeping with its mission and funding more genetic research.. All this “proposed” treatements, diets and biomedical approaches will benefit in the end, once we know the genetic changes/components of autism. Why would we not want that? Why would we fight against research.. Katie, I not sure why you are against our very mission!